Abstract 12641: Endothelial Cell Hspa12B Plays a Cardioprotective Role in Sepsis Induced Cardiac Dysfunction via the Release of MicroRNA Containing Exosomes

Abstract

Heat shock protein A12B (HSPA12B) is predominately expressed in endothelial cells and has been reported to contribute to angiogenesis. We hypothesized that HSPA12B plays a protective role in sepsis-induced cardiac dysfunction. Endothelial HSPA12B -/- (n=6) and wild type (WT, n=6) mice were subjected to cecal ligation and puncture (CLP)-induced sepsis. Sham surgical operation served as sham control (n=6). Cardiac function was examined by echocardiography before and 6 hour after CLP. In WT septic mice, ejection fraction (EF%) and fractional shortening (%FS) were significantly reduced by 34.8% and 43.1% (p<0.05), compared with control. HSPA12B -/- septic mice showed even greater decrements in EF% and FS% values (19.9% and 22.5%), when compared with WT septic mice. Serum levels of TNFα and IL-6 were higher in HSPA12B -/- septic mice than in WT septic mice. The expression of ICAM1 and VCAM1 in the myocardium of HSPA12B -/- septic mice was greater than in WT septic mice. Exosomes play an important role in cell-cell communication. In vitro data showed that exosomes isolated from the serum of HSPA12B -/- septic mice induced increased levels of TNFα and IL-6, NF-κB binding activity and TRAF6 ubiquitination in macrophages, when compared with WT septic exosomes. HSPA12B -/- septic exosomes contained significantly less microRNA-146a, which negatively regulates NF-κB signaling, when compared with WT septic exosomes. Endothelial cells (HUVEC) treated with HSPA12B -/- septic exosomes showed decreased expression of tight junction proteins (ZO-1and Occludin) and miR-126, which regulates the expression of adhesion molecules, when compared with WT septic exosomes treatment. In addition, the amounts of miR-146a and miR-126 in the exosomes from the serum of HSPA12B -/- septic mice were less than in the exosomes from WT septic mice. This is the first report that endothelial cell HSPA12B attenuates cardiac dysfunction in sepsis via secretion of exosomes and microRNA expression. We conclude that endothelial HSPA12B plays a cardioprotective role in sepsis via microRNA containing exosomes.